In recent years transmucosal delivery systems for biologically active substances have been studied more and more extensively. These systems are believed to have advantages that are not found with oral, transdermal or even intravenous delivery systems for such substances. Active agents, which require inconvenient intravenous administration due to poor oral bioavailability, are particular candidates for delivery via the oral mucosal tissues.
The buccal region of the mouth in the upper gum and inside cheek region provides a barrier to delivery that is more permeable than the skin itself and tends to be less variable between individuals. The membranes of the mouth are thin and permeable. The buccal mucosa is less sensitive to irritation than the nasal mucosa, which makes buccal delivery more acceptable to the patient. This is especially evident when the patient carries a virus infection which often—if followed by swelling and large secretions of the nasal mucosa—can effect the nasal transmucosal delivery with accompanying uncertainty of delivered dose. This makes buccal transmucosal delivery particularly attractive.
Another advantage for using this route is to avoid the first pass metabolism of the substance in the liver. Furthermore, the highly acidic conditions of the stomach and effects of proteases and their zymogens are avoided. The latter act in the intestines and are well known to inactivate and degrade different biologically active substances.
The main advantage of transmucosal delivery, however, is that biologically active substances can be absorbed directly into the bloodstream, allowing for rapid uptake of the substance into the body. Furthermore, by transmucosal delivery to the blood stream no active substance is lost due to first-pass liver metabolism. Thus, transmucosal delivery system provides quick passage through the mucous membranes of the mouth for faster absorption.
The buccal mucosa has a large area of smooth muscle and relatively immobile mucosa. This makes it a desirable region for transmucosal delivery systems. Accordingly, the buccal mucosa is considered more suitable for sustained delivery applications as well as delivery of less permeable molecules.
However, a rapid release of a biologically active substance is many times more desirable immediately after its administration. For example, a rapid release of the active substance is of crucial importance particularly with analgesics in order to achieve a rapid onset of the pain-relieving action. Likewise, people with sleeping disorders and those who are suffering from nausea need a fast onset of action when a biologically active substance is administrated. Another biologically active substance is nicotine, the effect of which people prefer to be instant when taken.
A frequently used alternative for smoking tobacco, especially in the Scandinavian countries and in the USA, has been the habit of using snuff made from tobacco and alternatively and specifically in the US, chewing tobacco. Chewing tobacco consists of the tobacco leaf with the stem removed. It is produced in the form of long strands of tobacco. The chewing tobacco is also available in small pouches that can be placed between the cheek and gum. Snuff, on the other hand, consists of the entire tobacco leaf, which is dried and granulated or finely cut. Various sweeteners and flavorings are added to these smokeless tobacco products.
Although some people prefer to sniff the snuff, many consumers takes a pinch of snuff (2-3 ml) from a can with moist powder and place it between the lip or cheek and gum and suck on it. The wet snuff is also produced as portion packed pouches that are placed likewise. While enjoying the texture of the fine grain tobacco, the nicotine is leached from the tobacco and delivered to the mucosa of the user.
Portion packed snuff is considered less damaging to the buccal mucosa than loose snuff. However, individuals consuming large amounts of snuff exhibit irritation of the overexposed mucosa and signs of peridontitis have been reported.
In addition, the Swedish tradition of taking wet snuff results in what many people experience as a strong nasty smell, which some people seem to be sensitive for. Furthermore, a pinch or a portion of snuff results in a bulging facial appearance which may look ill-mannered. Moreover, the snuff has a tendency to leak a stained liquid from the mouth during prolonged use. It may also leave unattractive tobacco spots when subsequently removed and thrown away in toilets, washbowls etc.
It is also well-known that chewing tobacco and snuff contain potentially harmful substances, such as volatile and nonvolatile nitrosamines, tobacco-specific N-nitrosamines, polynuclear aromatic hydrocarbons, and polonium-210. Thus, snuff consumers may be exposed to hazardous chemicals.
A number of tobacco substitutes have been developed and introduced to the market over the years as medical products, i.e. nicotine smoking deterrents. These products are used in nicotine replacement therapies, such as transdermal nicotine patches or chewing gums.
Nicotine patches, i.e. transdermal nicotine systems, provide a measured relatively slowly transferred dose of nicotine through the skin. The nicotine gum is a relatively faster acting form of replacement that acts through the mucous membrane of the mouth when the gum is chewed. Chewing stimulates secretion of saliva and the nicotine containing saliva causes irritation of the throat and when swallowed nicotine is lost due to first-pass liver metabolism. In addition, prolonged chewing results in a jaw discomfort, chewing gums are not always socially accepted, and the chewing in itself is considered impolite in certain cultures.
A nicotine nasal spray delivers the nicotine more quickly to the bloodstream as it is absorbed through the nose. The nasal spray is said to immediately relieve withdrawal symptoms and nicotine cravings. Such a therapy is available only by prescription. Nicotine inhalers were introduced in 1998 and are now available over the counter (OTC) in many countries.
WO 95/12399 shows a powdery pharmaceutical compositions that is especially intended for nasal administration. The compositions comprise nicotine and starch microspheres and show increased bioavailability of the drug when administered nasally.
In WO 91/09599 a smoking substitute composition is shown, which is intended for nasal, sub-lingual or buccal administration. The composition contains nicotine in the form of an inclusion complex with a cyclodextrin compound. This inclusion of nicotine in a cyclodextrin complex reflects the tendency of nicotine to evaporate if not bound or enclosed. The composition of WO 91/09599 also comprises excipients accepted for food or pharmaceutical use.
U.S. Pat. No. 4,369,172 shows a compressed medicinal solid unit dosage form which comprises a medicament and, as carrier, hydroxypropyl methylcellulose, ethylcellulose and/or sodium carboxymethylcellulose. The dosage forms are said to have a more prolonged release pattern than prior products of this type.
An oral nicotine dispenser is shown in U.S. Pat. No. 4,907,605, which comprises nicotine and a water insoluble polymeric substance formed of strips. The polymeric substance can be paper or cellulose, such as cellulose acetate, polyethylene, or polypropylene. The dispenser can be chewed or placed in the mouth to slowly release the sorbed nicotine into an oral environment.
Likewise, a slow release composition is shown in U.S. Pat. No. 3,845,217, which comprises a gum base, a buffering agent, and a complex containing nicotine bound to a synthetic cation exchanger. The complex is easy to handle and minimizes the personal risks during manufacturing, when it also acts as a lubricant.
The object of the invention is to provide a safe composition material that is adapted for rapid as well as slow release of a biologically active substance.